Recently, many studies have been done for the development of sustained release preparations with enteric coating base materials. However, when these known preparations are administered, the medicament contained therein is mostly released during passing the small intestine. In some kinds of medicaments, it is desired to be prepared in a sustained release preparation which can also release the medicament in the large intestine as well as in the small intestine and thereby can exhibit the medical activity for a long period. However, when a pharmaceutical preparation is orally administered, it passes through various pH range regions until reaching to the large intestine, that is, from the stomach which is a strong acidic region to the small intestine which is a neutral or alkaline region. Accordingly, it is a great task to find a pharmaceutical preparation which can reach to the large intestine of the lower digestive tract after passing through the digestive tract having variable pH ranges. Particularly, in order to prepare a pharmaceutical preparation which can release the active ingredient in the large intestine by administration once a day or to prepare a large intestine delivery preparation, it is required to keep the medicament without dissolution of the coating base material during passing through the ileum where the pH value raises to about 7.
Besides, when a pharmaceutical preparation is administered orally, it will usually take about 4 to 6 hours until reaching to the large intestine, and in case of a sustained release preparation which is formulated so as to administer once a day, it shall gradually release the medicament even after reached to the large intestine. Otherwise, a sufficiently high blood concentration of the medicament can not be maintained for 24 hours and hence the desired therapeutic effects can not be obtained. In other words, such a pharmaceutical preparation shall satisfy the requirements that it surely reaches to the large intestine and releases a sufficient amount of the medicament in the large intestine.
The conventional enteric coating base materials are mostly dissolve at a pH range lower than 7, and the enteric coating base materials soluble at around pH 7 are an acrylic coating material such as methacrylic acid-methyl methacrylate copolymer (Eudragit S, manufactured by Roehm) and a cellulosic coating material (e.g. hydroxypropyl methylcellulose acetate succinate (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.). These enteric coating materials are used for the coating in the form of a solution in an organic solvent or in the form of an aqueous dispersion. In view of the recent environmental restriction, an organic solvent is limited to use and hence it tends to use an aqueous coating material (e.g. an aqueous dispersion).
JP-60-43334 discloses an acrylic coating emulsion as a coating material, but when such an acrylic coating emulsion is used, the enteric coating film is contaminated with a polymerization initiator, a chain transfer agent, unreacted monomers, etc., which are not suitable for medication in view of safety.
JP-56-12614 discloses an aqueous dispersion comprising a cellulosic coating material having an average particle size of 100 μm or less and a plasticizer. Such an aqueous dispersion has less stability to heat and has defects that the coating base material aggregates and then precipitates.
JP-7-109219 discloses an enteric coating dispersion comprising an enteric coating material having an average particle size of 10 μm or less, a plasticizer and an anionic surfactant, which is stably dispersed for a long period without aggregation even by change of temperature. However, the hydroxypropyl methylcellulose acetate succinate (HPMCAS) used therein has a dissolving pH value of about 7 even at a grade of the highest dissolving pH value and it dissolves in a wide range of pH values. Accordingly, when a pharmaceutical preparation coated with such a coating material is administered orally, it dissolves in a small intestine and releases the medicament mostly in the small intestine.
JP-2-289512 discloses a pharmaceutical preparation comprising an enteric coated core granule and a large amount of an organic acid (30 to 50% by weight based on the weight of the core granules) so as to give an alkaline resistance even at a raised pH value. However, it is reported by Nykanen et al. (International Journal of Pharmaceutics, vol. 184, pp. 251–261, 1999) that even when a large amount of an acid is added to the core granule in an enteric coated granule preparation coated with HPMCAS, said preparation could not show the desired sustained release of the medicament (ibuprofen) in vivo test, and the blood level profile of the ibuprofen was similar to that in a granule to which no acid was added.